Testicular Cancer

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Testicular Cancer

NCCN Guidelines Index
Testicular Cancer TOC
Discussion
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™)
Testicular Cancer
Version 1.2011
NCCN.org
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Version 1.2011, 12/10/10 © National Comprehensive Cancer Network, Inc. 2010, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Printed by Tomasz Sarosiek on 1/3/2011 3:21:15 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.
NCCN Guidelines™ Version 1.2011 Panel Members
Testicular Cancer
Memorial Sloan-Kettering Cancer Center
Gary R. Hudes, MD † ‡
Fox Chase Cancer Center
Neeraj Agarwal, MD ‡
Huntsman Cancer Institute at the
University of Utah
Eric Jonasch, MD †
The University of Texas M. D. Anderson Cancer
Center
Clair Beard, MD §
Dana-Farber/Brigham and Women’s
Cancer Center
David Josephson, MD w
City of Hope Comprehensive Cancer Center
* Robert J. Motzer, MD/Chair † Þ
Sam Bhayani, MD w
Siteman Cancer Center at Barnes-Jewish
Hospital and Washington University
School of Medicine
Graeme B. Bolger, MD †
University of Alabama at Birmingham
Comprehensive Cancer Center
Michael A. Carducci, MD † Þ
The Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins
Sam S. Chang, MD w
Vanderbilt-Ingram Cancer Center
Toni K. Choueiri, MD † Þ
Dana-Farber/Brigham and Women’s
Cancer Center
Ellis G. Levine, MD †
Roswell Park Cancer Institute
Daniel W. Lin, MD w
University of Washington Medical
Center/Seattle Cancer Care Alliance
Kim A. Margolin, MD † ‡
Fred Hutchinson Cancer Research
Center/Seattle Cancer Care Alliance
M. Dror Michaelson, MD, PhD †
Massachusetts General Hospital Cancer Center
Thomas Olencki, DO †
The Ohio State University Comprehensive
Cancer Center - James Cancer Hospital and
Solove Research Institute
Roberto Pili, MD †
Roswell Park Cancer Institute
Steven L. Hancock, MD § Þ
Stanford Comprehensive Cancer Center
Continue
NCCN Guidelines Panel Disclosures
Discussion
Thomas W. Ratliff, MD †
St. Jude Children’s Research Hospital/University
of Tennessee Cancer Institute
Bruce G. Redman, DO †
University of Michigan Comprehensive Cancer
Center
Cary N. Robertson, MD w
Duke Comprehensive Cancer Center
Charles J. Ryan, MD † w
UCSF Helen Diller Family Comprehensive Cancer
Center
Joel Sheinfeld, MD w
Memorial Sloan-Kettering Cancer Center
Philippe E. Spiess, MD w
H. Lee Moffitt Cancer Center & Research Institute
Jue Wang, MD †
UNMC Eppley Cancer Center at
The Nebraska Medical Center
Richard B. Wilder, MD §
H. Lee Moffitt Cancer Center & Research Institute
† Medical oncology
‡ Hematology/hematology oncology
§ Radiotherapy/Radiation oncology
ф Diagnostic Radiology
£ Supportive Care including Palliative, Pain
Management, Pastoral care and Oncology social work
Þ Internal medicine
w Urology
* Writing committee member
NCCN Guidelines™ Version 1.2011 Table of Contents
Testicular Cancer
NCCN Testicular Cancer Panel Members
Summary of the Guidelines Updates
Workup, Primary Treatment and Pathologic Diagnosis (TEST-1)
Seminoma: Postdiagnostic Workup and Clinical Stage (TEST-2)
· Stage IA, IB (TEST-3)
· Stage IS (TEST-3)
· Stage IIA, IIB (TEST-3)
· Stage IIC, III (TEST-3)
Nonseminoma: Postdiagnostic Work-up and Clinical Stage (TEST-5)
· Stage IA, IB, IS (TEST-6)
· Stage IIA, IIB (TEST-7)
· Postchemotherapy Management (TEST-8)
· Postsurgical Management (TEST-9)
· Stage IIC, IIIA, IIIB, IIIC, and Brain Metastases (TEST-10)
· Follow-up for Nonseminoma (TEST-11)
Recurrence and Second Line Therapy (TEST-12)
Discussion
Clinical Trials: The NCCN
believes that the best management
for any cancer patient is in a clinical
trial. Participation in clinical trials is
especially encouraged.
To find clinical trials online at NCCN
member institutions, click here:
nccn.org/clinical_trials/physician.html
NCCN Categories of Evidence and
Consensus: All recommendations
are Category 2A unless otherwise
specified.
See NCCN Categories of Evidence
and Consensus
Staging (ST-1)
Risk Classification for Advanced Disease (TEST-A)
Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-B)
Second Line or Subsequent Chemotherapy Regimens for Metastatic Germ
Cell Tumors (TEST-C)
Principles of Surgery (TEST-D)
The NCCN Guidelines™ are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no
representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any
way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the
illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2010.
NCCN Guidelines™ Version 1.2011 Updates
Testicular Cancer
Discussion
Updates in Version 1.2011 of the NCCN Testicular Cancer Guidelines from Version 2.2010 include:
Testicular cancer
TEST-1
· Workup, “optional” was removed from testicular ultrasound.
· Pathologic diagnosis,
> “Pure” was added to seminoma germ cell tumor.
> “Includes mixed seminoma tumors and seminoma histology with elevated AFP” was added to nonseminoma.
· Footnote b, “Though rare, when a patient presents with rapidly increasing beta-hCG, symptoms related to disseminated disease and a testicular mass,
chemotherapy can be initiated immediately without a biopsy diagnosis” was added to the page.
Seminoma
TEST-2
· Postdiagnostic workup, “if elevated preoperatively” was removed from “repeat beta-hCG, LDH, AFP”.
· Footnote ‘c’ was modified, “Mediastinal primary site seminoma should be treated by risk status used for gonadal seminomas with...”.
· Footnote ‘e’ was modified, “Elevated values should be followed after orchiectomy with repeated determination to allow precise staging.” (Also for TEST-5)
TEST-3
· Stage IA, IB
> Surveillance:
7 “for pT1 or pT2 tumors” and “preferred” were added.
7 “horseshoe or pelvic kidney, inflammatory bowel disease, and prior RT” were removed.
> RT:
7 dose range was changed from 20-30 Gy to 20-25 Gy.
7 “preferred for pT3 tumors or tumors > 4 cm” was added.
7 “± ipsilateral iliac nodes” was removed.
> Footnote h, “In special circumstances, RT to ipsilateral iliac nodes may be administered (category 3)” is new to the page.
> Follow-up after surveillance or single dose carboplatin with abdominal/pelvic CT was changed from “at each visit” to “every 3-4 mo for years 1-3, every
6 mo for years 4-7, then annually at each visit up to 10 years” and chest x-ray was changed from “at alternate visits” to “as clinically indicated”.
· Stage IS
> RT dose range was changed from 25-30 Gy to 25 Gy.
> Follow-up after RT, chest x-ray was changed to “as clinically indicated”. Also for Stages IA, IB.
· Stage IIA, IIB
> RT dose range was changed from 35-40 Gy to 30-35 Gy.
> Chemotherapy, “BEP for 3 cycles” was added.
TEST-4
· Residual mass and normal markers
> “> 3 cm” was added as a qualifier to residual mass.
> PET scan not feasible was removed.
> PET scan, “approximately 6 wks post chemotherapy” was added.
> PET scan negative, “Consider RPLND, if technically feasible” replaced “surgery with biopsy”.
· “or residual mass £ 3cm” was added to “no residual mass and normal markers”.
· Follow-up, “abdominal/pelvic CT 4 mo post surgery then as clinically indicated” was changed to “Abdominal/pelvic CT, post RPLND: 3-6 mo, then as
clinically indicated” and “after all other primary management as clinically indicated”.
UPDATES
NCCN Guidelines™ Version 1.2011 Updates
Testicular Cancer
Discussion
Updates in Version 1.2011 of the NCCN Testicular Cancer Guidelines from Version 2.2010 include:
Nonseminoma
TEST-5
· Post diagnostic workup, “Chest CT if abnormal abdominal CT or abnormal chest x-ray” was removed and “± chest imaging” was added to “abdominal/
pelvic CT”.
· Footnote j, “PET scan is not clinically indicated for nonseminoma” was added to the page.
TEST-6
· Stage IB, primary chemotherapy, “BEP for 1 cycle” was added with a category 2B designation.
· Stage IS with persistent elevated markers has been redirected to TEST-10.
· Statement in the box was modified, “The EP and BEP chemotherapy regimens given at doses and schedules on TEST-B may be considered as category 1
compared with other chemotherapy regimens”. Also for TEST-7 and TEST-10.
TEST-7
· Stage IIA and IIB with persistent marker elevation have been redirected to TEST-10.
TEST-8
· For negative markers, “³ 1 cm” was added to residual mass.
· Negative markers, normal CT scan, no mass, “or residual mass < 1 cm” was added.
· “Bilateral” was added to “nerve-sparing RPLND.”
TEST-10
· Stage IS and Stage IIA,S1 and Stage IIB, S1 were added to the good risk category.
· Complete response, negative markers, “nerve-sparing RPLND” was changed to “bilateral RPLND ± nerve-sparing”.
TEST-11
· Surveillance after Stage IA, IB testicular cancer:
> “Months between abdominal/pelvic CT” was change to “Months between abdominal CT”.
> The intervals for each year were modified as follows:
7 Year 1 from 2-3 mo to 3-4 mo
7 Year 2 from 3-4 mo to 4-6 mo
7 Year 3 from 4 mo to 6-12 mo
7 Year 6+ from 12 mo to 12-24 mo
· Surveillance after complete response to chemotherapy and/or RPLND
> The intervals for each year were modified as follows:
7 Year 4 from 4 mo to 6 mo
TEST-12
· Footnote p, “It is preferred that patients with recurrent nonseminoma be treated at centers with expertise in the management of this disease” was added to
the page.
TEST-A:
· “For advanced disease” was added to the title “risk classification”.
· “Post-orchiectomy” was added under the title.
TEST-D
· Principles of Surgery is new to the guidelines.
UPDATES
NCCN Guidelines™ Version 1.2011
Testicular Cancer
WORKUP
Suspicious
testicular
mass
· H&P
· Alpha-fetoprotein (AFP)
· beta-hCG a
· LDH
· Chemistry profile
· Chest x-ray
· Testicular ultrasound
PRIMARY TREATMENT b
· Discuss sperm banking
· Radical inguinal orchiectomy
· Consider inguinal biopsy of
contralateral testis if:
> Suspicious ultrasound for
intratesticular abnormalities
> Cryptorchid testis
> Marked atrophy
Discussion
PATHOLOGIC DIAGNOSIS
Pure seminoma germ cell
tumor (pure seminoma
histology and AFP
negative; may have
elevated beta-hCG)
See
Postdiagnostic
Workup and
Clinical Stage
(TEST-2)
Nonseminomatous germ
cell tumor (includes
mixed seminoma tumors
and seminoma histology
with elevated AFP)
See
Postdiagnostic
Workup and
Clinical Stage
(TEST-5)
a Quantitative
analysis of beta subunit.
rare, when a patient presents with rapidly increasing beta-hCG, symptoms related to disseminated disease and a
testicular mass, chemotherapy can be initiated immediately without waiting for a biopsy diagnosis.
b Though
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
TEST-1
Testicular Cancer- Pure Seminoma
Pure seminoma germ cell tumor c
(pure seminoma histology and
AFP negative; d may have elevated
beta-hCG)
POSTDIAGNOSTIC WORKUP
· Abdominal/pelvic CT
· Chest CT if:
> Positive abdominal CT or
abnormal chest x-ray
· Repeat beta-hCG, LDH, AFP e
· Brain MRI, if clinically indicated
· Bone scan, if clinically indicated
Discussion
CLINICAL STAGE
Stage
IA, IB
See Primary Treatment
and Follow-up (TEST-3)
Stage
IS
Stage
IIA, IIB
Stage
IIC, III
c Mediastinal
primary site seminoma should be treated by risk status used for gonadal seminomas with
etoposide/cisplatin for 4 cycles or bleomycin/etoposide/cisplatin for 3 cycles.
d If AFP positive, treat as nonseminoma.
e Elevated values should be followed after orchiectomy with repeated determination to allow precise staging.
TEST-2
Testicular Cancer - Pure Seminoma
CLINICAL
STAGE
PRIMARY TREATMENT
FOLLOW-UP
Surveillance for pT1 or pT2 tumors
(category 1) (preferred)
or
Single agent carboplatin (category 1)
(AUC=7 x 1 cycle or AUC=7 x 2 cycles)
Stage
IA, IB
or
RT: Infradiaphragmatic (20-25 Gy) to include
para-aortic nodes h (category 1) (preferred
for pT3 tumors or tumors > 4 cm)
Stage
IS
RT: Infradiaphragmatic (25 Gy) to include
para-aortic ± ipsilateral iliac nodes
RT: Infradiaphragmatic (30-35 Gy) to include
para-aortic and ipsilateral iliac nodes
Stage
IIA, IIB
or
Consider primary chemotherapy for selected
stage IIB patients: g
EP for 4 cycles or BEP for 3 cycles
Good risk f
Primary chemotherapy: g
EP for 4 cycles (category 1)
or
BEP for 3 cycles (category 1)
Intermediate
risk f
BEP for 4 cycles (category 1)
Stage
IIC, III
f See
g See
Risk Classification (TEST-A).
Primary Chemotherapy Regimens for Germ Cell Tumors (TEST-B).
Discussion
· H&P, AFP, beta-hCG, LDH:
every 3-4 mo for years 1-3,
every 6 mo for years 4-7, then annually
· Abdominal/pelvic CT every 3-4 mo for
years 1-3, every 6 mo for years 4-7,
then annually at each visit up to 10
years; chest x-ray as clinically
indicated
Recurrence, treat
according to extent of
disease at relapse
· H&P + AFP, beta-hCG, LDH: every 3-4
mo for year 1,
every 6 mo for year 2, then annually
· Pelvic CT annually for 3 years (for
patients status post only para-aortic RT)
chest x-ray as clinically indicated
Recurrence, treat
disease at relapse
· H&P + chest x-ray, AFP, beta-hCG, LDH:
every 3-4 mo for years 1-3,
every 6 mo for year 4, then annually
· Abdominal CT at month 4 of year 1
Recurrence, treat
disease at relapse
See Post Chemotherapy Management
See Post Chemotherapy Management
EP = Etoposide/cisplatin
BEP = Bleomycin/etoposide/cisplatin
h In
special circumstances, RT to ipsilateral iliac nodes may be administered (category 3).
TEST-3
Testicular Cancer - Pure Seminoma
STAGE IIB, IIC, III AFTER PRIMARY
TREATMENT WITH CHEMOTHERAPY
POST
CHEMOTHERAPY
MANAGEMENT
No residual mass
or residual mass
£ 3cm and normal
markers
· Chest, abdominal,
pelvic CT scan
· Serum tumor
markers
Residual
mass
(> 3 cm)
and
normal
markers
Discussion
FOLLOW-UP
Surveillance
Negative
Surveillance
Positive
Consider RPLND, if
technically feasible
or
Second line
chemotherapy i
or
RT (category 2B)
PET scan
(approximately
6 wks post
chemotherapy)
Progressive
disease (growing
mass or rising
markers)
· H&P + chest x-ray, AFP,
beta-hCG, LDH:
every 2 mo for year 1
every 3 mo for year 2,
every 6 mo for year 3
and 4, then annually
· Abdominal/pelvic CT
> Post RPLND:
3-6 mo, then as
clinically indicated
> After all other
primary management
as clinically indicated
· PET scan as clinically
indicated
Recurrence,
See Second
Line Therapy
(TEST-12)
See Second Line Therapy for
Nonseminoma (TEST-12)
RPLND = retroperitoneal lymph node dissection
i See
Second Line or Subsequent Chemotherapy Regimens for Metastatic Germ Cell Tumors (TEST-C).
TEST-4
Testicular Cancer - Nonseminoma
POSTDIAGNOSTIC WORKUP j
Discussion
CLINICAL STAGE
Stage IA, IB, IS:
See Primary
Treatment (TEST-6)
Nonseminomatous germ cell
tumor (includes mixed seminoma
tumors and seminoma histology
with elevated AFP)
· Abdominal/pelvic CT ± chest imaging
· Repeat beta-hCG, LDH, AFP e
· Brain MRI, if clinically indicated
· Bone scan, if clinically indicated
Stage IIA, IIB:
See Primary
Treatment (TEST-7)
Stage IIC, IIIA, IIIB, IIIC,
and brain metastasis:
(TEST-10)
e Elevated
j PET
values should be followed after orchiectomy with repeated determination to allow precise staging.
scan is not clinically indicated for nonseminoma.
TEST-5
CLINICAL STAGE
PRIMARY TREATMENT
Surveillance
(in compliant patients)
Stage IA
Discussion
See Follow-up for
or
Nerve-sparing RPLND k,l
See Postsurgical
Management (TEST-9)
See Postsurgical
Management (TEST-9)
or
BEP for 2 cycles or
BEP for 1 cycle (category 2B)
Stage IB
See Postchemotherapy
Management (TEST-8)
or
Surveillance (only if T2,
compliant patients [category 2B])
Stage IS
Persistent
marker
elevation
See Follow-up for
See Primary Treatment (TEST-10)
The EP and BEP chemotherapy regimens given
at doses and schedules on TEST-B may be
considered as category 1 compared with other
chemotherapy regimens.
g See
lymph node dissection (RPLND) is recommended within 4 weeks of CT scan and 7-10 days of markers (category 2B).
l See Principles of Surgery (TEST-D).
k Retroperitoneal
TEST-6
CLINICAL STAGE
Discussion
PRIMARY TREATMENT
or
Markers negative
Primary chemotherapy g (category 2B):
Stage IIA
Persistent marker
elevation
See Postchemotherapy
Management (TEST-8)
Nerve-sparing RPLND j,k
Lymph node metastases,
within lymphatic drainage
sites (landing zone positive)
Markers negative
Multifocal, symptomatic, or
lymph node metastases with
aberrant lymphatic drainage
Stage IIB
See Postsurgical
Management (TEST-9)
Persistent marker
elevation
See Postsurgical
Management (TEST-9)
or
See
Postchemotherapy
Management
(TEST-8)
g See
l See Principles of Surgery (TEST-D).
k Retroperitoneal
TEST-7
Discussion
POSTCHEMOTHERAPY MANAGEMENT
Negative markers,
residual mass (³ 1 cm)
Nerve-sparing bilateral RPLND k,l
or
Surveillance
(category 2B)
Stage IB, IIA, IIB
treated with primary
chemotherapy
See Follow-up for
Negative markers,
normal CT scan, no
mass or residual
mass (< 1 cm)
Nerve-sparing bilateral RPLND k,l
(category 2B)
or
Surveillance
(category 2B)
k Retroperitoneal
l See
Principles of Surgery (TEST-D).
TEST-8
Discussion
POSTSURGICAL MANAGEMENT
pN0
Surveillance
Compliant
pN1
Surveillance (preferred)
or
Chemotherapy: g
EP for 2 cycles
or BEP for 2 cycles
Noncompliant
Chemotherapy: g
EP for 2 cycles
or BEP for 2 cycles
Stage IA, IB, IIA, IIB
treated with nervesparing RPLND
Compliant
Chemotherapy (preferred): g
or
Surveillance
Noncompliant
Chemotherapy: g
EP for 2 cycles
or BEP for 2 cycles
pN2
pN3
See Follow-up for
Nonseminoma
(TEST-11)
Chemotherapy (preferred): g
EP for 4 cycles
or BEP for 3 cycles
g See
TEST-9
CLINICAL
STAGE
Good risk f
Stage IS
Stage IIA, S1
Stage IIB, S1
Stage IIC
Stage IIIA
PRIMARY TREATMENT
Primary
chemotherapy: g
EP for 4 cycles
or
BEP for 3 cycles
Complete
response,
negative
markers
Intermediate
risk f
Stage IIIB
Primary
chemotherapy: g
BEP for 4 cycles
Partial response,
residual masses o
with normal AFP
and beta-hCG levels
Poor risk f
Stage IIIC
Clinical trial
(preferred)
or
Primary
chemotherapy: g
BEP for 4 cycles
or
VIP for 4 cycles in
selected patients n
Incomplete
response o
Brain
metastases m
Primary chemotherapy g + RT
± surgery, if clinically indicated
f See
Risk Classification (TEST-A).
i See Second Line or Subsequent Chemotherapy Regimens for Metastatic
Germ Cell Tumors (TEST-C).
k Retroperitoneal lymph node dissection (RPLND) is recommended within 4
weeks of CT scan and 7-10 days of markers (category 2B).
g See
Discussion
Surveillance (category 2B)
or
Bilateral RPLND k,l ± nerve-sparing (category 2B)
Teratoma or
necrosis
Surgical
resection of
all residual
masses
See Second Line
Therapy (TEST-12)
Residual embryonal,
yolk sac,
choriocarcinoma, or
seminoma elements
Surveillance
See Follow-up
for
Nonseminoma
(TEST-11)
Chemotherapy
for 2 cycles
(EP g or TIP i or
VIP g/VeIP i)
TIP = Paclitaxel/ifosfamide/cisplatin
VeIP = Vinblastine/ifosfamide/cisplatin
VIP = Etoposide/ifosfamide/cisplatin
l See
Principles of Surgery (TEST-D).
should receive adequate treatment for brain metastases, in addition to
cisplatin-based chemotherapy.
n Patients who may not tolerate bleomycin.
o There is limited predictive value for PET scan for residual masses.
m Patients
TEST-10
Discussion
FOLLOW-UP FOR NONSEMINOMA
Surveillance After Complete Response to
Chemotherapy and/or RPLND
Surveillance for Stage IA, IB Testicular Cancer
Year
Months between visits,
markers, chest x-ray
Months between
abdominal CT
Months between visits,
markers, chest x-ray
(category 2B for
chest x-ray frequency)
Months between
abdominal/pelvic CT *
1
1-2
3-4
Year
2
2
4-6
1
2-3
6
3
3
6-12
2
2-3
6-12
4
4
6-12
3
3-6
12
5
6
12
4
6
12
6+
12
12-24
5
6-12
12
6+
12
As clinically indicated
* CT scans apply only to patients
treated with chemotherapy alone.
For patients who are post RPLND,
a postoperative baseline CT scan
is recommended and additional
CT scans as clinically indicated.
Recurrence, See Salvage
Therapy (TEST-12)
TEST-11
RECURRENCE p
SECOND LINE THERAPY
Favorable prognosis:
· Low markers
· Low volume
· Complete response
on first-line therapy
· Testis primary
· Chemotherapy i
> Conventional
dose therapy
(VeIP or TIP)
or
> High-dose
chemotherapy
Incomplete
response
or relapse
· Chemotherapy i
> High-dose chemotherapy
(preferred if not previously given)
or
> Clinical trial
· Surgical salvage should be
considered if solitary site
· Best supportive care
Relapse
Complete
response
Prior
chemotherapy
Unfavorable prognosis:
· Incomplete response
· High markers
· High volume
· Extratesticular
primary
· Late relapse
No prior
chemotherapy
Discussion
Follow-up
Palliative
chemotherapy i
or
RT
· Chemotherapy i
> Clinical trial (preferred) or
> Conventional dose therapy (VeIP or TIP) or
> High-dose chemotherapy (category 2B)
· Surgical salvage should be considered if
solitary site
· Best supportive care
Treat as per risk status on TEST-10
VeIP = Vinblastine/ifosfamide/cisplatin
TIP = Paclitaxel/ifosfamide/cisplatin
i See
p It
Second Line or Subsequent Chemotherapy Regimens for Germ Cell Tumors (TEST-C).
is preferred that patients with recurrent nonseminoma be treated at centers with expertise in the management of this disease.
TEST-12
Discussion
RISK CLASSIFICATION FOR ADVANCED DISEASE
(post orchiectomy) 1
Risk Status
Nonseminoma
Seminoma
Good Risk
Testicular or retroperitoneal primary tumor
and
No nonpulmonary visceral metastases
and
Post-orchiectomy markers- all of:
AFP < 1,000 ng/mL
hCG < 5,000 iu/L
LDH < 1.5 x upper limit of normal
Any primary site
and
and
Normal AFP
Any hCG
Any LDH
Intermediate Risk
Testicular or retroperitoneal primary tumor
and
and
Post-orchiectomy markers- any of:
AFP 1,000-10,000 ng/mL
hCG 5,000-50,000 iu/L
LDH 1.5-10 x upper limit of normal
Any primary site
and
Nonpulmonary visceral metastases
and
Normal AFP
Any hCG
Any LDH
Poor Risk
Mediastinal primary tumor
or
Nonpulmonary visceral metastases
or
Post-orchiectomy markers- any of:
AFP > 10,000 ng/mL
hCG > 50,000 iu/L
LDH > 10 x upper limit of normal
No patients classified as poor
prognosis
Source: Figure 4 from the International Germ Cell Cancer Collaborative Group: International Germ Cell Consensus Classification:
A Prognostic Factor-Based Staging System for Metastatic Germ Cell Cancers. J Clin Oncol 1997;15(2):594-603. Reprinted with
permission of the American Society of Clinical Oncology.
1 Markers
used for risk classification are post-orchiectomy.
TEST-A
Discussion
PRIMARY CHEMOTHERAPY REGIMENS
FOR GERM CELL TUMORS
EP
Etoposide 100 mg/m 2 IV on Days 1 - 5
Cisplatin 20 mg/m 2 IV on Days 1 - 5
Repeat every 21 days 1
BEP
Etoposide 100 mg/m 2 IV on Days 1 - 5
Bleomycin 30 units IV weekly on Days 1, 8, and 15*
VIP
Etoposide 75 mg/m 2 IV on Days 1-5
Mesna 120 mg/m 2 slow IV push before ifosfamide on Day 1, then
Mesna 1200 mg/m 2 IV continuous infusion on Days 1-5
Ifosfamide 1200 mg/m 2 on Days 1-5
Cisplatin 20 mg/m 2 IV on Days 1-5
*Some NCCN Institutions administer bleomycin on a 2, 9, 16 schedule.
1 Xiao
H, Mazumdar M, Bajorin DF, et al. Long-term follow-up of patients with good-risk germ cell tumors treated with etoposide and cisplatin. J Clin Oncol
1997;15:2553-2558.
2 Saxman SB, Finch D, Gonin R & Einhorn LH. Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in
favorable-prognosis germ-cell tumors: The Indiana University Experience. J Clin Oncol 1998;16:702-706.
3 Nichols CR, Catalano PJ, Crawford ED, et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of
advanced disseminated germ cell tumors: An Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B
Study. J Clin Oncol 1998;16:1287-1293.
TEST-B
Discussion
SECOND LINE OR SUBSEQUENT CHEMOTHERAPY REGIMENS FOR
METASTATIC GERM CELL TUMORS
Conventional dose chemotherapy regimens
VeIP
Vinblastine 0.11 mg/kg IV Push on Days 1 - 2
Mesna 400 mg/m 2 IV every 8 hours on Days 1 - 5
Ifosfamide 1200 mg/m 2 IV on Days 1 - 5
TIP
Paclitaxel 250 mg/m 2 IV on Day 1
Ifosfamide 1500 mg/m 2 IV on Days 2 - 5
Mesna 500 mg/m 2 IV before ifosfamide, and then 4 and 8 hours
after each ifosfamide dose on Days 2 - 5
High-dose chemotherapy regimens
Carboplatin 700 mg/m 2 (Body Surface Area) IV
Etoposide 750 mg/m 2 IV
Administer 5, 4, and 3 days before peripheral blood stem cell
infusion for 2 cycles 6
Paclitaxel 200 mg/m 2 IV over 24 hours
Ifosfamide 2000 mg/m 2 over 4 hours with mesna protection
Repeat every 14 days for 2 cycles followed by
Carboplatin AUC 7 - 8 IV over 60 minutes Days 1 - 3
Etoposide 400 mg/m 2 IV Days 1 - 3
Administer with peripheral blood stem cell support at 14 - 21 day
intervals for 3 cycles 7
Palliative chemotherapy regimen
GEMOX
Gemcitabine 1000 mg/m 2 IV on Days 1 and 8 followed by
Oxaliplatin 130 mg/m 2 IV on Day 1
Repeat every 21 days 3,4
or
Gemcitabine 1250 mg/m 2 IV on Days 1 and 8 followed by
Oxaliplatin 130 mg/m 2 IV on Day 1
See Chemotherapy References (TEST-C 2 of 2)
TEST-C
1 of 2
Discussion
SECOND LINE OR SUBSEQUENT CHEMOTHERAPY REGIMENS FOR
METASTATIC GERM CELL TUMORS
CHEMOTHERAPY REFERENCES
1 Loehrer
PJ Sr, Lauer R, Roth BJ, et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern
Med 1988;109:540-546.
2 Kondagunta GV, Bacik J, Donadio A, et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed
testicular germ cell tumors. J Clin Oncol 2005;23:6549-6555.
3 Pectasides D, Pectasides M, Farmakis D, et al. Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study.
Ann Oncol 2004;15:493-497.
4 Kollmannsberger C, Beyer J, Liersch R, et al. Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory
germ cell cancer: A study of the German Testicular Cancer Study Group. J Clin Oncol 2004; 22(1):108-114.
5 De Giorgi U, Rosti G, Aieta M, et al. Phase II study of oxaliplatin and gemcitabine salvage chemotherapy in patients with cisplatin-refractory nonseminomatous
germ cell tumor. Eur Urol 2006;50:893-894.
6 Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 2007;357:340-348.
7 Kondagunta GV, Bacik J, Sheinfeld J, et al. Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors.
J Clin Oncol 2007;25:85-90.
TEST-C
2 of 2
Discussion
PRINCIPLES OF SURGERY
· RPLND is the standard approach to the surgical management of nonseminoma germ cell tumor (NSGCT) in both primary and
post-chemotherapy setting.
· A template dissection or a nerve-sparing approach to minimize the risk of ejaculatory disorders should be considered in patients
undergoing primary RPLND for stage I nonseminoma.
· The “split and roll” technique in which lumbar vessels are identified and sequentially ligated allows resection of all lymphatic tissue
around and behind the great vessels (aorta, IVC) and minimizes the risk of an in-field recurrence.
Post-chemotherapy setting
· Referral to high volume centers should be considered for surgical resection of masses post-chemotherapy.
· Completeness of resection is an independent and consistent predictive variable of clinical outcome. In post-chemotherapy RPLND,
surgical margins should not be compromised in an attempt to preserve ejaculation. Additional procedures and resection of adjacent
structures may be required.
· Post-chemotherapy RPLND is indicated in metastatic NSGCT patients with a residual retroperitoneal mass following systemic
chemotherapy and normalized post-chemotherapy serum tumor markers.
· A full bilateral template RPLND should be performed in all patients undergoing RPLND in the post-chemotherapy setting, with the
boundaries of dissection being the renal hilar vessels (superiorly), ureters (laterally), and the common iliac arteries (inferiorly).
TEST-D
NCCN Guidelines™ Version 1.2011 Staging
Testicular Cancer
Discussion
Table 1
American Joint Committee on Cancer (AJCC)
TNM Staging System for Testis Cancer (7th ed., 2010)
Primary Tumor (T)*
The extent of primary tumor is usually classified after radical
orchiectomy, and for this reason, a pathologic stage is assigned.
pTX
pT0
pTis
pT1
pT2
pT3
pT4
Primary tumor cannot be assessed
No evidence of primary tumor (e.g. histologic scar in
testis)
Intratubular germ cell neoplasia (carcinoma in situ)
Tumor limited to the testis and epididymis without
vascular/lymphatic invasion; tumor may invade into the
tunica albuginea but not the tunica vaginalis
Tumor limited to the testis and epididymis with
vascular/lymphatic invasion, or tumor extending through
the tunica albuginea with involvement of the tunica
vaginalis
Tumor invades the spermatic cord with or without
vascular/lymphatic invasion
Tumor invades the scrotum with or without
vascular/lymphatic invasion
*Note: Except for pTis and pT4, extent of primary tumor is classified
by radical orchiectomy. TX may be used for other categories in the
absence of radical orchiectomy.
Used with the permission of the American Joint Committee on Cancer
(AJCC), Chicago, Illinois. The original and primary source for this information
is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by
Springer Science and Business Media LLC (SBM). (For complete information
and data supporting the staging tables, visit www.springer.com.) Any citation
or quotation of this material must be credited to the AJCC as its primary
source. The inclusion of this information herein does not authorize any reuse
or further distribution without the expressed, written permission of Springer
SBM, on behalf of the AJCC.
Regional
Clinical
NX
N0
N1
Lymph Nodes (N)
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Metastasis with a lymph node mass 2 cm or less in
greatest dimension; or multiple lymph nodes, none more
than 2 cm in greatest dimension
N2
Metastasis with a lymph node mass, more than 2 cm but
not more than 5 cm in greatest dimension; or multiple
lymph nodes, any one mass greater than 2 cm but not
more than 5 cm in greatest dimension
N3
Metastasis with a lymph node mass more than 5 cm in
greatest dimension
Pathologic (pN)
pNX
Regional lymph nodes cannot be assessed
pN0
No regional lymph node metastasis
pN1
Metastasis with a lymph node mass 2 cm or less in
greatest dimension and less than or equal to five nodes
positive, none more than 2 cm in greatest dimension
pN2
Metastasis with a lymph node mass more than 2 cm but
not more than 5 cm in greatest dimension; or more than
five nodes positive, none more than 5 cm; or evidence of
extranodal extension of tumor
pN3
Metastasis with a lymph node mass more than 5 cm in
greatest dimension
Distant Metastasis (M)
M0
No distant metastasis
M1
Distant metastasis
M1a
Nonregional nodal or pulmonary metastasis
M1b
Distant metastasis other than to nonregional lymph
nodes and lung
ST-1
NCCN Guidelines™ Version 1.2011 Staging
Testicular Cancer
Discussion
Table 1 (continued)
American Joint Committee on Cancer (AJCC)
TNM Staging System for Testis Cancer (7th ed., 2010)
ANATOMIC STAGE/PROGNOSTIC GROUPS
Group
T
N
M
S (Serum Tumor
Markers)
Stage 0
pTis
N0
M0
S0
Stage I
pT1-4
N0
M0
SX
Stage IA
pT1
N0
M0
S0
Stage IB
pT2
N0
M0
S0
PT3
N0
M0
S0
PT4
N0
M0
S0
Stage IS
Any pT/TX
N0
M0
S1-3
Stage II
Any pT/Tx
N1-3
M0
SX
Stage IIA Any pT/TX
N1
M0
S0
Any pT/TX
N1
M0
S1
Stage IIB Any pT/TX
N2
M0
S0
Any pT/TX
N2
M0
S1
Stage IIC Any pT/TX
N3
M0
S0
Any pT/TX
N3
M0
S1
Stage III
Any pT/TX
Any N
M1
SX
Stage IIIA Any pT/TX
Any N
M1a
S0
Any pT/TX
Any N
M1a
S1
Stage IIIB Any pT/TX
N1-3
M0
S2
Any pT/TX
Any N
M1a
S2
Stage IIIC Any pT/TX
N1-3
M0
S3
Any pT/TX
Any N
M1a
S3
Any pT/Tx
Any N
M1b
Any S
Serum Tumor Markers (S)
SX
Marker studies not available or not performed
SO
Marker study levels within normal limits
S1
LDH < 1.5 x N* and
hCG (mIu/mL) < 5,000 and
AFP (ng/ml) < 1,000
S2
LDH 1.5-10 x N or
hCG (mIu/mL) 5,000-50,000 or
AFP (ng/ml) 1,000-10,000
S3
LDH > 10 x N or
hCG (mIu/mL) > 50,000 or
AFP (ng/ml) > 10,000
*N indicates the upper limit of normal for the LDH assay.
Used with the permission of the American Joint Committee on Cancer
(AJCC), Chicago, Illinois. The original and primary source for this information
is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by
Springer Science and Business Media LLC (SBM). (For complete information
and data supporting the staging tables, visit www.springer.com.) Any citation
or quotation of this material must be credited to the AJCC as its primary
source. The inclusion of this information herein does not authorize any reuse
or further distribution without the expressed, written permission of Springer
SBM, on behalf of the AJCC.
ST-2
Testicular Cancer
Discussion
This discussion is being updated to correspond with the
newly updated algorithm. Last updated 04/26/10
NCCN Categories of Evidence and Consensus
Category 1: The recommendation is based on high-level evidence
(e.g. randomized controlled trials) and there is uniform NCCN
consensus.
Category 2A: The recommendation is based on lower-level evidence
and there is uniform NCCN consensus.
Category 2B: The recommendation is based on lower-level evidence
and there is nonuniform NCCN consensus (but no major
disagreement).
Category 3: The recommendation is based on any level of evidence
but reflects major disagreement.
All recommendations are category 2A unless otherwise noted.
Overview
An estimated 8,400 new cases of testicular cancer will be diagnosed in
the United States in 2009.1 Germ cell tumors (GCTs) comprise 95% of
malignant tumors arising in the testes. These tumors also occur
occasionally in extragonadal primary sites, but they are still managed
the same as testicular GCTs. Although GCTs are relatively uncommon
tumors that comprise only 2% of all human malignancies, they
constitute the most common solid tumor in men between the ages of 15
and 34 years. In addition, the worldwide incidence of these tumors has
more than doubled in the past 40 years.
Several risk factors for GCT development have been identified,
including prior history of a GCT, positive family history, cryptorchidism,
Discussion
testicular dysgenesis, and Klinefelter’s syndrome. GCTs are classified
as seminoma or nonseminoma. Nonseminomatous tumors often
include multiple cell types, including embryonal cell carcinoma,
choriocarcinoma, yolk sac tumor, and teratoma. Teratomas are
considered to be either mature or immature depending on whether
adult-type differential cell types or partial somatic differentiation, similar
to that present in the fetus, is found. Rarely, a teratoma histologically
resembles a somatic cancer, such as sarcoma or adenocarcinoma, and
is then referred to as a teratoma with malignant transformation.
The serum tumor markers alpha-fetoprotein (AFP), lactate
dehydrogenase (LDH), and human chorionic gonadotropin (hCG) are
critical in diagnosing the presence of tumors, determining prognosis,
and assessing treatment outcome. These should be determined before,
during, and after treatment and throughout the follow-up period. AFP is
a serum tumor marker produced by nonseminomatous cells (embryonal
carcinoma, yolk-sac tumor) and may be seen at any stage. The
approximate half-life of AFP is 5 to 7 days. A nonseminoma, therefore,
is associated with elevated serum concentrations of AFP. An elevated
serum concentration of hCG, which has a half-life of approximately 1–3
days, may also be present with seminomatous and nonseminomatous
tumors. Seminomas are occasionally associated with an elevated
serum concentration of hCG but not an elevated concentration of AFP.
Nonseminoma is the more clinically aggressive tumor. When both a
seminoma and elements of a nonseminoma are present, management
follows that for a nonseminoma. Therefore, the diagnosis of a
seminoma is restricted to pure seminoma histology and a normal serum
concentration of AFP.
More than 90% of patients diagnosed with GCTs are cured, including
70% to 80% of patients with advanced tumors who are treated with
MS-1
Testicular Cancer
chemotherapy. A delay in diagnosis correlates with a higher stage at
presentation. Standard therapy has been established at essentially all
stages of management and must be closely followed to ensure the
potential for cure.
Clinical Presentation
A painless solid testicular mass is pathognomonic for testicular tumor.
More often, patients present with testicular discomfort or swelling
suggestive of epididymitis or orchitis. A trial of antibiotics may be given
in this circumstance, but persistent tenderness, swelling, or any
palpable abnormality warrants further evaluation using testicular
ultrasound. Although testicular ultrasound is optional if the diagnosis is
obvious from the physical examination, it is performed in most
instances to define the lesion.
If an intratesticular mass is identified, further evaluation includes
measurement of the serum concentrations of alpha-fetoprotein (AFP),
lactate dehydrogenase (LDH), and beta-human chorionic gonadotropin
(beta-hCG) and a chest radiograph. Elevated values of beta-hCG, LDH,
or AFP should be followed up with repeated tests to allow precise
staging. Serum concentrations of hCG and LDH may be elevated in
patients with seminoma. An elevated AFP level indicates
nonseminoma, and the patient should be managed accordingly. If a
GCT is found, an abdominopelvic computed tomographic (CT) scan is
performed. A chest CT may be indicated if the abdominopelvic CT
shows retroperitoneal adenopathy or the chest radiograph shows
abnormal results. Inguinal orchiectomy is considered the primary
treatment for most patients who present with a suspicious testicular
mass.2 An open inguinal biopsy of the contralateral testis is not
routinely performed, but can be considered when a cryptorchid testis or
marked atrophy is present.3 Biopsy may also be considered if a
Discussion
suspicious intratesticular abnormality, such as a hypoechoic mass or
macrocalcifications, is identified on ultrasound. In contrast, if
microcalcifications without any other abnormality can be observed,
testicular biopsy is not necessary. These studies, and others as
clinically indicated, determine the clinical stage and direct patient
management. If clinical signs of metastases are present, magnetic
resonance imaging (MRI) of the brain and bone scanning are indicated.
Further management is dictated by histology, a diagnosis of seminoma
or nonseminoma, and stage. Consideration of sperm banking must be
discussed with the patients before undergoing any therapeutic
intervention that may compromise fertility, including radiation therapy,
surgery, and chemotherapy.
Seminoma
In 1997, the International Germ Cell Cancer Consensus Group
(IGCCCG) defined a prognostic factor-based classification system
based on identification of some clinically independent prognostic
features such as extent of disease and levels of serum tumor markers
post orchidectomy. The risk groups have been incorporated into the
American Joint Committee on Cancer staging for GCTs. This
classification categorized patients with seminoma and non-seminoma
GCT into good-, intermediate-, or poor-risk groups.4
Seminoma Stages IA and IB
For patients with disease in stages IA and IB, the category 1 options
include radiotherapy or chemotherapy with single dose carboplatin
(discussed further in the subsequent paragraphs). However these two
options can potentially lead to late morbidity. Therefore, surveillance is
also an option for these patients. The NCCN panel recommends
surveillance (category 1) for patients who have undergone previous
radiotherapy, who have a horseshoe kidney, or who have inflammatory
MS-2
Testicular Cancer
Discussion
bowel disease and also for selected patients with T1 or T2 disease
(category 2B) who are committed to long-term follow-up. Between 15%
and 20% of patients with seminoma, experience relapse during
surveillance if they do not undergo adjuvant radiation therapy after
orchiectomy.5 The median time to relapse is approximately 12 months,
but relapses can occur more than 5 years after orchiectomy. Relapse
occurring after surveillance essentially represents a prolongation in the
lead time of treatment. Therefore, these patients are treated according
to the stage at relapse.
1,148 patients were reported at the 2008 ASCO Annual Meeting.8 In an
intent-to-treat analysis, the relapse free rates at 5 years were 94.7% for
the carboplatin arm and 96% for the radiotherapy arm (hazard ratio,
1.25; P = .37), There was a significant difference in the rate of new
germ cell tumors (2 on carboplatin versus 15 on radiation therapy),
giving a hazard ratio (HR) of 0.22 (95% CI 0.05, 0.95 p=0.03). The
authors conclude that a single dose of carboplatin is less toxic and just
as effective in preventing disease recurrence as adjuvant radiotherapy
in men with stage I seminoma after orchiectomy.
Radiation (category 1) (20–30 Gy) is given to the infradiaphragmatic
area, including para-aortic lymph nodes and may include the ipsilateral
ileoinguinal nodes.6 Prophylaxis to the mediastinum is not provided,
because relapse rarely occurs at this site. Patients for whom radiation
therapy is generally not given include those with patients at higher risk
for morbidity from radiation therapy. These patients include those with
stages IA and IB with a horseshoe or pelvic kidney, with inflammatory
bowel disease, and who have undergone prior radiation therapy.
Follow up for patients treated with radiotherapy includes a history and
physical, with measurement of post orchiectomy serum tumor markers,
performed every 3 to 4 months for the first year, and 6 months for the
second year and annually thereafter. Annual pelvic CT is recommended
for 3 years for patients who underwent para-aortic RT. More intense
follow-up is recommended for patients not undergoing radiation therapy
- a history and physical, with measurement of post orchiectomy serum
tumor markers, should be performed every 3 to 4 months for the first 3
years, and 6 months for the next 3 years and annually thereafter. An
abdominal/pelvic CT scan is recommended at each visit and chest
x-ray at alternate visit for up to 10 years for those treated with a single
dose of carboplatin or those under surveillance.
A single dose of carboplatin is as an alternative to radiation therapy
(category 1) for patients with stages IA and IB disease. Oliver et al7
reported on the results of a trial that randomized 1477 patients with
stage 1 testicular cancer to undergo either radiotherapy or one injection
of carboplatin. In the study, carboplatin was administered at a dose of
AUC X 7 (AUC=area under the dose-time concentration curve). The
doses were given intravenously and calculated by a formula based on
the AUC estimate of drug disappearance from the body. The dose was
calculated by the formula 7 X (glomerular filtration rate [GFR, mL/min] +
25) mg. With a median follow-up of 4 years, the relapse-free survivals
for both groups were similar. Because late relapses and secondary
germ cell tumors can occur beyond 5 and 10 years, the authors
continued follow-up of these patients. The updated follow-up results of
Seminoma Stage 1S
Patients with stage IS are treated with radiation (25-30 Gy) to the
infradiaphragmatic area, including para-aortic lymph nodes with or
without radiation to the ipsilateral ileo inguinal nodes.6 Follow-up
recommendations are similar to that of patients with stages 1A and 1B.
If advanced, disseminated disease is suspected, a full course of
chemotherapy is administered according to guidelines for good risk
GCT.
MS-3
Testicular Cancer
Seminoma Stages IIA and IIB
Stage IIA is defined as disease measuring less than 2 cm in diameter
on CT scan, and stage IIB as disease measuring 2 to 5 cm in maximum
diameter. For patients with stage IIA or IIB disease, 35 to 40 Gy is
administered to the infradiaphragmatic area, including para-aortic and
ipsilateral iliac lymph nodes. As in the management of stage I disease,
prophylactic mediastinal radiation therapy is not indicated.9 Surveillance
is not an option for patients with stage IIA or IIB disease with relative
contraindications for radiation. In stage IIB chemotherapy with 4
courses of etoposide and cisplatin (EP) is an alternative
recommendation.
Follow-up for patients with stage IIA or IIB disease includes a history
and physical, with measurement of serum tumor markers, should be
performed every 3 to 4 months for the first 3 years, and 6 months for
the fourth year and annually thereafter. Abdominal CT is recommended
after 4 months during the first year.
Seminoma Stages IIC and III
Patients with stage IIC or III disease are those considered at good or
intermediate risk. All stage IIC and stage III disease is considered good
risk except for stage III disease with non-pulmonary visceral
metastases, which is considered intermediate risk. Standard
chemotherapy is used for both groups of patients, but for patients with
good risk, either 4 cycles of EP 10,11 are recommended or 3 cycles of
bleomycin, etoposide, and cisplatin (BEP).12-14 In contrast, 4 cycles of
BEP are recommended for those with intermediate risk disease.15 All
these options are category 1 recommendations.
After initial chemotherapy, patients with stage IIC and III are evaluated
with serum tumor markers and a CT scan of the chest abdomen and
pelvis. Patients are then classified according to the presence or
Discussion
absence of a residual mass and the status of serum tumor markers.
Patients with no residual mass and normal markers need no further
treatment and undergo surveillance. In patients with a residual mass
with normal markers, a positron emission tomography (PET) scan is
recommended to assess for residual viable tumor.16 To reduce the
incidence of false-positive results, the PET scan is typically performed
no less then 6 weeks after completion of chemotherapy. Notably,
granulomatous disease, such as sarcoid, is a frequent source of
false-positive results. If the PET scan is negative, no further treatment
is needed however, the patient should be observed closely for
recurrence. If it is positive, then biopsy should be considered followed
by surgical excision (category 2B) or second line chemotherapy.
Alternatively, the patient can be treated with radiation therapy (category
2B). Cisplatin-based combination chemotherapy is used for second line
treatment. The recommended regimens are four cycles of TIP
(paclitaxel, ifosfamide, cisplatin) 17 or four cycles of VeIP (vinblastine,
ifosfamide, cisplatin).18,19
For patients who cannot undergo a PET scan, post-chemotherapy
management is based on CT scan findings. Controversy exists
regarding optimal management when the residual mass is greater than
3 cm, because approximately 25% of these patients have a viable
seminoma or previously unrecognized nonseminoma.20 Options include
surgery (category 2B), radiation therapy (category 2B), and
observation. If surgery is selected, the procedure consists of resection
of the residual mass or multiple biopsies. A full bilateral or modified
retroperitoneal lymph node dissection (RPLND) is not performed
because of its technical difficulty in patients with seminoma and
because of extensive fibrosis, which may be associated with severe
morbidity.21 If the residual mass is 3 cm or less, patients should
undergo observation, which is detailed in TEST-4.
MS-4
Testicular Cancer
Recurrent disease is initially treated according to the stage at
recurrence. Second line chemotherapy therapy is recommended for
patients with rising serum tumor markers or a growing mass detected
on CT scan. Second line therapy for seminoma and nonseminoma is
similar and is discussed further in the section on nonseminoma.
Approximately 90% of patients with advanced seminoma are cured with
cisplatin-containing chemotherapy.22
Patients with seminoma arising from an extragonadal site, such as the
mediastinum, are treated with standard chemotherapy regimens
according to risk status.
Nonseminoma
The risk classification for nonseminoma into good-, intermediate- and
poor-risk groups by the IGCCCG 4 is defined in TEST-A.
Stage-dependent treatment options after inguinal orchiectomy include
surveillance, chemotherapy, and RPLND. Although the timing of the
RPLND may vary, most patients with nonseminoma will undergo an
RPLND for either diagnostic or therapeutic purposes at some point
during treatment. The major morbidity associated with bilateral
dissection is retrograde ejaculation, resulting in infertility.
Nerve-dissection techniques preserve antegrade ejaculation in 90% of
cases.23 Template dissections, which avoid the contralateral
sympathetic chain, postganglionic sympathetic fibers, and hypogastric
plexus, preserve ejaculation in approximately 80% of patients. In
general, an open nerve-sparing RPLND rather than a laparoscopic
RPLND is recommended for therapeutic purposes. For example, a
concern exists that a laparoscopic RPLND may result in false-negative
results caused by inadequate sampling, and no published reports focus
on the therapeutic efficacy of a laparoscopic dissection. Because the
recommended number of cycles of chemotherapy is based on the
Discussion
number of positive nodes identified, inadequate sampling may lead to
partial treatment.24
Nonseminoma Stage IA
Two management options exist for patients with stage IA disease after
orchiectomy: (1) surveillance (in compliant patients) 25-27 or (2) open
nerve-sparing RPLND.
The cure rate with either approach exceeds 95%. However, the high
cure rate associated with surveillance depends on adherence to
periodic follow-up examinations and subsequent chemotherapy for the
20% to 30% of patients who experience relapse.
Noncompliant patients are treated with open RPLND. The open nerve
sparing RPLND is typically performed within 4 weeks of a CT scan and
within 7 to 10 days of repeat serum marker testing to ensure accurate
presurgical staging. If the dissected lymph nodes are not involved with
a tumor (pN0), no adjuvant chemotherapy is given after open nerve
sparing RPLND. However, if the resected lymph nodes involve tumor,
the decision whether to use adjuvant chemotherapy is based on the
degree of nodal involvement and the ability of the patient to comply with
surveillance. Chemotherapy is preferred over surveillance in patients
with pN2 or pN3 disease. Recommended regimens include either EP or
BEP; 2 cycles of either regimen are recommended for patients with pN1
or pN2 disease. 28-34 For patients with pN3 disease, longer courses of
chemotherapy with 4 cycles of EP or 3 cycles of BEP (preferred) is
recommended.
The follow-up examinations in those electing surveillance in the current
NCCN guidelines include an abdominopelvic CT scan every 2 to 3
months for the first year and every 3 to 4 months during the second
year. Serum marker determination and the chest radiograph should be
MS-5
Testicular Cancer
Discussion
performed every 1 to 2 months during the first year and every 2 months
during the second year.
the patient and the physician must be compliant with follow-up
recommendations.
Nonseminoma Stage IB
Nonseminoma Stage IS
After orchidectomy, either open nerve sparing RPLND or chemotherapy
with 2 cycles of BEP (category 2B) are adjuvant treatment options to
reduce the risk of relapse in patients with stage IB disease.31,35.
Patients with stage IS disease exhibit a persistent elevation of serum
tumor markers post orchiectomy but no radiographic evidence of
disease. These patients are treated with standard chemotherapy with
either 4 cycles of EP or 3 cycles of BEP. Either regimen is preferable to
initial open nerve sparing RPLND because these patients nearly always
have disseminated disease.37,38 Primary chemotherapy may be
followed by open nerve sparing RPLND or surveillance.
A trial by Albers et al randomized stage I patients after orchiectomy, to
undergo RPLND (n = 191) or one adjuvant course of BEP.(n = 191) 36
After a median follow-up of 4.7 years two relapses were reported in the
group of patients treated with one course of adjuvant BEP and 13
patients with relapse in the arm treated with RPLND (P = 0.0011). This
study indicates that one course of BEP is active in patients and could
be an option in patients unable to tolerate the toxicity of treatment. The
results of this study are promising and merits further investigation. The
current standard of care practiced by most NCCN institutions is two
courses of BEP.
The subsequent management following primary open nerve sparing
RPLND for patients with IB is similar to that described for stage IA in
the section above. Subsequent management following primary
chemotherapy may be open nerve sparing RPLND or surveillance (if
the patient is compliant).
Surveillance alone may be offered to compliant patients with T2
disease (category 2B). Vascular invasion is a significant predictor of
relapse when orchiectomy is followed by surveillance alone.2
Surveillance is generally not recommended for T2 disease with
vascular invasion because of the 50% chance of relapse. Exceptions
are made according to individual circumstances in compliant patients.
When surveillance is opted in selected patients with T2 disease, both
Nonseminoma Stages IIA and IIB
Treatment for patients with stage IIA nonseminoma depends on post
orchiectomy serum tumor marker levels. When the levels of tumor
markers are persistently elevated, patients are treated with
chemotherapy with 4 cycles of EP or 3 cycles of BEP, followed by open
nerve sparing RPLND or surveillance.
For patients with stage IIA disease, when the tumor marker levels are
normal, 2 treatment options are available. Patients can undergo primary
chemotherapy with 4 cycles of EP or 3 cycles of BEP (category 2B),
followed by open nerve sparing RPLND 39 or surveillance. This
treatment is considered particularly appropriate if the patient has
multifocal disease. Alternatively, the patient can undergo primary nervesparing RPLND with adjuvant chemotherapy (two cycles of EP or BEP).
Treatment for patients with stage IIB disease depends on both post
orchiectomy tumor marker levels and radiographic findings. When
tumor markers are negative, the CT findings determine the proper
course of treatment. If abnormal radiographic findings are limited to
sites within the lymphatic drainage in the retroperitoneum (i.e., the
MS-6
Testicular Cancer
landing zone), two management options are available. One option is to
perform open nerve sparing RPLND and to consider adjuvant
chemotherapy as described for patients with stage IIA disease. The
second option is to treat with primary chemotherapy with either 4 cycles
of EP or 3 cycles of BEP, followed by open nerve sparing RPLND or
surveillance.
Both options, of primary chemotherapy or primary RPLND are
comparable options in terms of outcome but side-effects and toxicity
are different.40 The reported relapse free survival with either approach
is close to 98%.41-47
If metastatic disease (based on radiographic findings) is not confined to
the lymphatic drainage (i.e., multifocal lymph node metastases outside
the lymphatic drainage sites), or if there is persistent marker elevation,
similar primary chemotherapy (4 cycles of EP or 3 cycles of BEP) is
recommended. Initial open RPLND is not recommended in this
situation.
Subsequent management of Stage IIA and IIB
Following primary chemotherapy, either surveillance or an open nerve
sparing RPLND is recommended depending on the presence of a
residual mass.
Following primary open nerve sparing RPLND, surveillance may be
opted for depending on the number of positive lymph nodes identified
and patient compliance. For example, surveillance is opted in pN0
patients and is preferred in compliant patients with pN1 disease,
whereas chemotherapy is preferred for pN2 disease and surveillance is
not recommended for pN3 disease. Recommended chemotherapy for
pN1 and pN2 consists of 2 cycles of BEP or EP, resulting in a nearly
Discussion
100% relapse-free survival rate.45 For pN3, the guidelines recommend
4 cycles of EP or 3 cycles of BEP.
Nonseminoma Stages IIC and III
Patients with stage IIC and stage III disease are treated with primary
chemotherapy regimens based on risk status. Also, patients with an
extragonadal primary site, whether retroperitoneal or mediastinal, are
treated with initial chemotherapy. Classifications of risk status emerged
from chemotherapy research designed to decrease the toxicity of the
regimens while maintaining maximal efficacy.
Initial chemotherapy combinations studied in the 1970s contained
cisplatin, vinblastine, and bleomycin and achieved a complete response
in 70% to 80% of patients with metastatic GCTs. These regimens were
associated with serious adverse effects, including neuromuscular toxic
effects, death from myelosuppression or bleomycin-induced pulmonary
fibrosis, and Raynaud’s phenomenon.
The high cure rate and toxicity associated with cisplatin, vinblastine,
and bleomycin regimens resulted in efforts to stratify patients and tailor
therapy according to risk. Extent of disease and levels of post
orchiectomy serum tumor markers were identified as important
prognostic features, and models were developed to stratify patients.
The International Germ Cell Cancer Consensus Classification was
developed and incorporated the risk groups into the American Joint
Committee on Cancer staging for GCTs. This classification categorized
patients as good-, intermediate-, or poor-risk.4
Good-Risk (Stages IIC and IIIA) Nonseminoma
Treatment programs for good-risk GCTs were designed to decrease
toxicity while maintaining maximal efficacy. Randomized clinical trials
showed that this was achieved by substituting etoposide for
MS-7
Testicular Cancer
vinblastine,48,49 and either eliminating or reducing the dose of
bleomycin.48,50 Presently, 2 regimens are considered standard
treatment programs in the United States for good-risk GCTs: 4 cycles of
EP or 3 cycles of BEP. Either regimen is well tolerated and cures
approximately 90% of patients with good risk.51
Intermediate- (Stage IIIB) and Poor-Risk (Stage IIIC)
Nonseminoma
Between 20% and 30% of all patients with metastatic GCTs are not
cured with conventional cisplatin therapy. Poor prognostic features at
diagnosis that can be used to identify these patients include
nonpulmonary visceral metastases and high serum tumor marker
concentrations or mediastinal primary site in patients with
nonseminoma.52 In patients with these prognostic factors, clinical trials
are directed at improving efficacy.
For patients with intermediate risk, the cure rate is approximately 70%
with standard therapy using 4 cycles of BEP.53,54
In patients with poor-risk GCTs (stage IIIC), less than one half
experience a durable complete response to 4 cycles of BEP, and
therefore treatment in a clinical trial is preferred.51 The panel
recommends 4 cycles of etoposide, ifosfamide, and cisplatin (VIP
regimen) for patients who may not tolerate bleomycin.55 Due to the less
than favorable prognosis of patients in the poor-risk group, treating
them in the context of a clinical trial is the preferred recommendation by
the NCCN Testicular Cancer panel.
Primary chemotherapy using cisplatin-based regimen plus radiotherapy
is indicated for patients in whom brain metastases are detected. If
clinically indicated, surgery should also be performed. Surgery can be
performed if clinically indicated such as in the case of a solitary
Discussion
metastasis, depending on the systemic state of the disease, the
histology of the primary tumor and the location of the metastasis.
Postchemotherapy Management for Stages IIC and IIIA–IIIC
Nonseminoma
At the conclusion of induction chemotherapy, CT scans of the abdomen
and pelvis are indicated, along with serum tumor marker assays. PET
scans for residual disease have limited predictive value. If a complete
response is found and the tumor markers are negative, 2 management
options exist: surveillance (category 2B) or an open nerve sparing
RPLND (category 2B).
If residual disease is found and the serum tumor markers (AFP and
beta-HCG) have normalized, then all sites of residual disease are
resected. If only necrotic debris or mature teratoma is encountered, no
further therapy is necessary and patients must be put under
surveillance. In the 15% of patients who have viable residual cancer, 2
cycles of conventionally dosed chemotherapy (EP, VelP
[paclitaxel/ifosfamide/cisplatin], or TIP [vinblastine/ifosfamide/cisplatin])
are administered.
After patients are rendered disease-free, standard observation is
initiated. Patients who experience an incomplete response to first-line
therapy or unresectable disease at surgery are treated with second-line
therapy.
Second Line Therapy for Metastatic Germ Cell Tumors
Patients who do not experience a durable complete response to
first-line therapy can be divided into those with a favorable or
unfavorable prognosis based on prognostic factors.
MS-8
Testicular Cancer
Standard second line therapy includes conventional dose
chemotherapy or high dose chemotherapy. Prognostic factors can be
used in deciding whether a patient is a candidate for conventional dose
therapy or high-dose therapy with stem cell support as a second line
option. Favorable prognostic factors to conventional dose second-line
chemotherapy include a testicular primary site, prior complete response
to first-line therapy, low levels of post orchiectomy serum tumor
markers, and low-volume disease.56 The conventional dose regimen
include cisplatin and ifosfamide combined with either vinblastine or
paclitaxel.57 If the patient experiences an incomplete response or
relapses after second-line conventional dose chemotherapy, the
preferred third-line option would be high-dose chemotherapy with
autologous stem cell support.
Unfavorable prognostic features include incomplete response to firstline treatment, high levels of serum markers, high volume disease and
presence of extratesticular primary tumor. Patients with a testicular
primary site and rising post orchiectomy serum tumor markers during
first-line therapy are usually considered for high-dose programs.
Chemotherapy options for patients with poor prognostic features
include chemotherapy in the context of a clinical trial (preferred);
conventional-dose second line therapy; high-dose chemotherapy plus
autologous stem cell support (category 2B). Alternatively, the patients
may be put on best supportive care or salvage surgery if feasible.
Discussion
undergoes surgical resection.61 Other options are participation in a
clinical trial or best supportive care.
Subsequent Therapy for Patients with Persistent or Recurrent
Metastatic Germ Cell Tumors
The more advanced the disease, the higher the likelihood of
recurrence. All patients with either persistent or recurrent disease
should be considered for palliative chemotherapy or radiation therapy.
A recommended palliative chemotherapy for patients with intensively
pretreated, cisplatin-resistant, or refractory germ cell tumor is
combination of gemcitabine with oxaliplatin (category 2A
recommendation). This recommendation is based on data from phase II
studies.62-64 These studies investigated the efficacy and the toxicity of
gemcitabine and oxaliplatin (GEMOX) in patients with relapsed or
cisplatin-refractory GCTs. The results showed that
oxaliplatin-gemcitabine combination is a safe for patients with
cisplatin-refractory testicular GCTs and may offer a chance of long-term
survival.62-64 Toxicity of GEMOX was found to be primarily
hematological and generally manageable.
The high dose regimens include high-dose carboplatin plus etoposide
followed by autologous stem cell transplant 58,59 or paclitaxel, ifosfamide
followed by high dose carboplatin plus etoposide with stem cell
support.60 For patients who do not experience complete response to
second line high-dose therapy, the disease is nearly always incurable;
the only exception is the rare patient with elevated serum tumor
markers and a solitary site of metastasis (usually retroperitoneal) that
MS-9
Testicular Cancer
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REF-4

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